{
  "abstract": "Background: Brain-wide association effects are commonly overestimated in psychiatric neuroimaging research, leading to low replicability and generalizability of findings, and ultimately to poor translation to clinical utility. Cross-validation is currently not standardly used in univariate neuroimaging analyses but could pose a potential counteracting measure for this problem.\n\nMethods: We systematically evaluated the benefit of a cross-validation procedure to expose inflated effect size estimates in mass-univariate voxel-based analysis, using body mass index (BMI) as an example predictor for gray matter. A total of n = 3401 MRI scans from a psychiatric cohort were used to investigate the impact of applying cross-validation on effect size estimates across a range of sample sizes and across different localizations with a range of underlying pooled effect sizes.\n\nResults: BMI was negatively associated with gray matter density with a maximum underlying effect size of R ² p = 0.036 (in the full sample of n = 3401). However, without cross-validation, effects were substantially overestimated in small samples, with effect sizes ranging up to R ² p = 0.535. Even with an underlying null-effect, effect size estimates up to R ² p = 0.429 were reached in samples with n = 25. Applying cross-validation revealed that these inflated effects in small samples did not generalize to novel data. A minimum sample size of n = 100 was required for largest brain-wide effects to start generalizing, while samples with n = 400 were needed for smaller effects to generalize. This ‘point of initial generalizability’ was not reached for underlying null effects, even with the maximum available sample of n = 3401.\n\nConclusions: Results suggest that cross-validation is an effective measure to expose overestimated effects in small samples and thus could help to counteract low replicability and generalizability in brain-wide mass-univariate association studies. Open-source code is provided for practical implementation.",
  "abstract_shown": true,
  "affiliations": [
    "Department of Psychiatry and Neurosciences, Campus Benjamin Franklin, Charité-Universitätsmedizin Berlin, Berlin, Germany. janik.goltermann@charite.de",
    "German Center for Mental Health (DZPG), Site Berlin, Potsdam, Germany. janik.goltermann@charite.de",
    "Institute for Translational Psychiatry, University of Münster, Münster, Germany. janik.goltermann@charite.de",
    "Institute for Translational Psychiatry, University of Münster, Germany",
    "Institute for Machine Learning in Medicine (focus area psychiatry), University of Münster, Münster, Germany",
    "Institute for Translational Psychiatry, University of Münster, Münster, Germany",
    "Otto Creutzfeldt Center for Cognitive and Behavioral Neuroscience, University of Münster, Germany",
    "Cooperative Brain Imaging Center - CoBIC, Goethe University Frankfurt, Frankfurt, Germany",
    "Department of Psychiatry, Psychosomatic Medicine, and Psychotherapy, Goethe University Frankfurt, University Hospital, Frankfurt, Germany",
    "Department of Psychiatry and Neurosciences, Campus Benjamin Franklin, Charité-Universitätsmedizin Berlin, Berlin, Germany",
    "German Center for Mental Health (DZPG), Site Berlin, Potsdam, Germany",
    "Department of Psychiatry and Psychotherapy, Jena University Hospital, Germany",
    "Institute for Translational Neuroscience, University of Münster, Münster, Germany",
    "Institute for Translational Neuroscience, University of Münster, Germany",
    "Department of Clinical Psychology and Psychotherapy, Marburg University, Marburg, Germany",
    "Department of Neurology, Kepler University Hospital, Johannes Kepler University Linz, Linz, Austria",
    "Faculty of Mathematics and Computer Science, University of Münster, Münster, Germany",
    "Institute for Biomagnetism and Biosignalanalysis, Universitätsklinikum Münster, Münster, Germany",
    "Institute for Geoinformatics, University of Münster, Münster, Germany",
    "Faculty of Mathematics and Computer Science, University of Münster, Germany",
    "Institute for Geoinformatics, University of Münster, Germany",
    "Institute of Epidemiology and Social Medicine, University of Münster, Münster, Germany",
    "Institute of Epidemiology and Social Medicine, University of Münster, Germany",
    "Department of Psychiatry and Psychotherapy, Marburg University, Marburg, Germany",
    "Department of Psychiatry and Psychotherapy, University of Marburg, Germany",
    "Northwell Health, New Hyde Park, USA",
    "ORIGAMI Neuro Data Science Laboratory, McConnell Brain Imaging Centre, Montreal Neurological Institute, Faculty of Medicine and Health Sciences, McGill University, Montreal, QC, Canada",
    "Center for Mind, Brain and Behavior (CMBB), Universities of Marburg, Gießen and Darmstadt, Marburg, Germany",
    "Core-Facility Brainimaging, Faculty of Medicine, Marburg University, Marburg, Germany",
    "Department of Neurology, Jena University Hospital, Jena, Germany",
    "Department of Psychiatry and Psychotherapy, Jena University Hospital, Jena, Germany",
    "German Center for Mental Health (DZPG), Site Jena Magdeburg Halle, Germany",
    "Department of Neurology, Jena University Hospital, Germany",
    "Center for Intervention and Research on adaptive and maladaptive brain Circuits underlying mental health (C-I-R-C), Jena-Magdeburg-Halle, Germany",
    "German Center for Mental Health (DZPG), Site Jena-Magdeburg-Halle, Germany",
    "Center for Intervention and Research on Adaptive and Maladaptive Brain Circuits Underlying Mental Health (C-I-R-C), Site Jena Magdeburg Halle, Germany",
    "Department of Psychiatry, Medical School and University Medical Center OWL, Protestant Hospital of the Bethel Foundation, Bielefeld University, Bielefeld, Germany"
  ],
  "article_type": null,
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      "name": "Alexandra Winter",
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      "name": "Kira Flinkenflügel",
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      "name": "Ramona Leenings",
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      "name": "Carlotta Barkhau",
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      "name": "Jan Ernsting",
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      "name": "Klaus Berger",
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      "name": "Heike Minnerup",
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      "name": "Benjamin Straube",
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      "name": "Nina Alexander",
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      "name": "Hamidreza Jamalabadi",
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      "name": "Frederike Stein",
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      "name": "Katharina Brosch",
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      "name": "Adrian Wroblewski",
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      "name": "Florian Thomas‐Odenthal",
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      "name": "Paula L Usemann",
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      "name": "Lea Teutenberg",
      "orcid": "0009-0002-7783-8461"
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      "name": "Julia‐Katharina Pfarr",
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      "name": "Tilo T. J. Kircher",
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      "name": "Christian Gaser",
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  "doi": "10.1038/s41398-026-04529-x",
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  "issns": [
    "2158-3188"
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  "language": "en",
  "licence": "CC-BY-4.0",
  "licence_label": "CC BY 4.0",
  "licence_source": "article",
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  "pdf_url": "https://www.nature.com/articles/s41398-026-04529-x.pdf",
  "pmcid": null,
  "pmid": "42982783",
  "published": "2026-11-04",
  "publisher": "Springer Science and Business Media LLC",
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  "subjects": [
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  "title": "Counteracting the overestimation of effect size in mass-univariate brain-wide association studies using cross-validation",
  "title_text": "Counteracting the overestimation of effect size in mass-univariate brain-wide association studies using cross-validation",
  "type": "peer-reviewed",
  "updated_at": "2026-11-06T13:20:36Z",
  "url": "https://research.draconitic.com/paper/a8hpzhvb5sxrx",
  "venue": "Translational Psychiatry",
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